Detection Of Impurities Research Articles

Insight into Analytical Techniques for the Detection of Nitrosamine Impurities: A Review

Nitrosamine impurities in pharmaceutical products have increased attention for safety in the direction of the use of various drugs. Nitrosamines are the class of compounds which represents nitroso group attached to an amine (R1N(-R2)-N=0). Nitrosamines are molecules that have a nitroso group connected to an amine (R1N(-R2)-N=0). Controlling cancer-causing contaminants in pharmaceutical products is critical for predicting and avoiding the carcinogenic risk of medicine in people. According to recent findings, nitrosamine impurities have increased the medicinal product's carcinogenic risk. The literature search was accomplished using PubMed, Google scholar, and the Cochrane library to identify relevant scientific articles using various sensitive techniques and analytical instruments for the detection of nitrosamine impurities from the years 1981 to 2022. The search terms included nitrosamine detection techniques, formation of nitrosamine, HPLC technique for nitrosamine detection, GC-MS/MS, GC-MS/MS, GC-MS-Head space, and GC-QTOF technique for nitrosamine detection, LC-MS/MS technique for nitrosamine detection, The literature search included 29 scientific articles from the English lamnguage, including original research and standard guidelines intended to review all the sensitive techniques for detection of nitrosamine impurities in pharmaceutical products. The current review aims to discuss the highly sensitive, cost effective, accurate and precise methods for the detection of various nitrosamine contaminations in the pharmaceutical products.

A lightweight network of near cotton‐coloured impurity detection method in raw cotton based on weighted feature fusion

AbstractThe objective is to improve the recognition rate of white and near cotton‐coloured impurities in raw cotton against a single white visible light source background. A lightweight detection network model without anchor boxes based on improved YOLO v4‐tiny is proposed in this paper based on weighted feature fusion (WFF). The WFF strategy was used to improve the detection accuracy of the improved YOLO v4‐tiny algorithm. Meanwhile, to address the disadvantage that the anchor boxes obtained by the K‐means algorithm clustering do not have global features, the anchor‐free and tiny decoupled head schemes are used instead of the traditional coupled detection head. The improved algorithm was validated on the PASCAL VOC2012 dataset and the self‐built raw cotton impurity dataset collected by high‐speed camera. On the raw cotton impurity test set, compared to the original YOLO v4‐tiny model, the mean average precision (mAP) and frames per second (FPS) of the improved model increased by 10.35% and 6.9%, respectively. The proposed model detects white and near cotton‐coloured impurities with an accuracy of up to 98.78% and 98.00%. The experimental results show that the proposed method can effectively detect and identify impurities in raw cotton, which is of great practical significance for foreign matter detection and identification in cotton.

Long period grating fibre sensor for detection of impurities infesting smart polymer composites

An analysis of using Long Period Grating Fibre Sensors (LPGFS) as detectors of Smart Composite Polymer Material (SCPM) impurity infestation is presented. The analysis is performed by using a self-developed simulation package. The investigated LPGFS is operated as mounted into a self-interference (SILPG) setup embedded in polymer matrix. The LPGFS constitutes the feedback loop of an automation system. The simulation results are compared with experimental ones and a good agreement between the two kinds of data being observed. The analysis is aiming to an optimized design of this type of sensors for accomplishing the proposed task which means enlarged applications range in aeronautics, industry, medicine and defence of SCPM.

An Improved YOLOv5 Model: Application to Mixed Impurities Detection for Walnut Kernels.

Impurity detection is an important link in the chain of food processing. Taking walnut kernels as an example, it is difficult to accurately detect impurities mixed in walnut kernels before the packaging process. In order to accurately identify the small impurities mixed in walnut kernels, this paper established an improved impurities detection model based on the original YOLOv5 network model. Initially, a small target detection layer was added in the neck part, to improve the detection ability for small impurities, such as broken shells. Secondly, the Tansformer-Encoder (Trans-E) module is proposed to replace some convolution blocks in the original network, which can better capture the global information of the image. Then, the Convolutional Block Attention Module (CBAM) was added to improve the sensitivity of the model to channel features, which make it easy to find the prediction region in dense objects. Finally, the GhostNet module is introduced to make the model lighter and improve the model detection rate. During the test stage, sample photos were randomly chosen to test the model's efficacy using the training and test set, derived from the walnut database that was previously created. The mean average precision can measure the multi-category recognition accuracy of the model. The test results demonstrate that the mean average precision (mAP) of the improved YOLOv5 model reaches 88.9%, which is 6.7% higher than the average accuracy of the original YOLOv5 network, and is also higher than other detection networks. Moreover, the improved YOLOv5 model is significantly better than the original YOLOv5 network in identifying small impurities, and the detection rate is only reduced by 3.9%, which meets the demand of real-time detection of food impurities and provides a technical reference for the detection of small impurities in food.

A Bioanalytical Method for Quantification of N-nitrosodimethylamine (NDMA) in Human Plasma and Urine with Different Meals and following Administration of Ranitidine

Control of N-nitrosoamine impurities is important for ensuring the safety of drug products. Findings of nitrosamine impurities in some drug products led FDA to develop new guidance providing recommendations for manufacturers towards prevention and detection of nitrosamine impurities in pharmaceutical products. One of these products, ranitidine, also had a published in vivo study, which has since been retracted by its authors, suggesting a potential for in vivo conversion of ranitidine to the probable human carcinogen, N-nitrosodimethylamine (NDMA). FDA subsequently initiated a randomized, double-blind, placebo-controlled, crossover clinical investigation to assess the potential for in vivo conversion of ranitidine to NDMA with different meals. A bioanalytical method toward characterization of NDMA formation was needed as previously published methods did not address potential NDMA formation after biofluid collection. Therefore, a bioanalytical method was developed and validated as per FDA's Bioanalytical Method Validation guidance. An appropriate surrogate matrix for calibration standards and quality control sample preparation for both liquid matrices (human plasma and urine) was optimized to minimize the artifacts of assay measurements and monitor basal NDMA levels. Interconversion potential of ranitidine to NDMA was monitored during method validation by incorporating the appropriate quality control samples. The validated methods for NDMA were linear from 15.6 pg/mL to 2000 pg/mL. Low sample volumes (2 mL for urine and 1 mL for plasma) made this method suitable for clinical study samples and helped to evaluate the influence of ranitidine administration and meal types on urinary excretion of NDMA in human subjects.

Dietary Supplements with Proline—A Comprehensive Assessment of Their Quality

Dietary supplements are food products commonly used worldwide to obtain nutritional and physiological effects. They can contain a wide variety of active substances and can be administered for health and disease. Their use can be beneficial if justified, and their quality is adequate. Unfortunately, data on the quality of supplements is scarce. As part of this work, we assess the quality of seven dietary supplements containing proline. The preparations were produced in the EU and the USA. The quality assessment consisted of the detection of potential impurities, the determination of the content of the main ingredient, and the release of proline. The technique used to analyse impurities and proline (Pro) content was liquid chromatography coupled with tandem mass spectrometry. We detected five contaminants. The main ingredient content was in the range of 73-121% in capsules and 103-156% in tablets. Five of the seven analysed dietary supplements released below 80% Pro (for each tablet/capsule at pH 1.2). One of the supplements may be inactive because a very low release of Pro was reported. The results, we hope, will increase consumer awareness of the quality of these preparations and result in a change in the regulations governing the marketing of these preparations, at least by making release testing mandatory.

Nile blue as reporter dye in salt aggregation based-colorimetric aptasensors for peptide, small molecule and metal ion detection

Herein, we report a novel approach for the design of a colorimetric aptasensor, relying on a Dye Salt Aggregation-based Colorimetric Oligonucleotide assay (DYSACO assay). This method is based on the use of an intercalating agent, Nile Blue (NB), whose aggregation capacities (and thus modification of its absorption spectrum) are drastically amplified by adding salts to the working solution. The presence of an aptamer could protect NB from such aggregation process due to its intercalation into double-stranded DNA and/or interaction with nucleobases. In response to the addition of the specific ligand, the competition between NB and the target for binding to the aptamer occurs, resulting in an increase in the dye salt aggregation and then in the blue-to-blank color change of the solution. The proof-of-principle was demonstrated by employing the anti-l-tyrosinamide aptamer and the assay was successfully applied to the trace enantiomer detection, allowing the detection of an enantiomeric impurity down to approximately 2% in a non-racemic sample. Through a reversed mechanism based on the increased capture of NB by DNA upon analyte binding, the sensing platform was further demonstrated for the Hg(II) detection. Water samples of different origin were spiked with Hg(II) analyte at final range concentrations comprised between (0.5–15 μM). An excellent overall recovery of 122 ± 14%; 105 ± 14%; 99 ± 9%; was respectively obtained from river, tap and mineral water, suggesting that the sensor can be used under real sample conditions. The assay was also shown to work for sensing the ochratoxin A and d-arginine vasopressin compounds, revealing its simplicity and generalizability potentialities.

Spectral properties inspired image enhancement for crystalline polymer powder impurity detection

Crystalline polymer powder inevitably incorporates certain impurities, including decomposed polymers or foreign particles. An essential criterion for assessing the quality of polymers is the quantity of contaminants in the powder. However, it is challenging to discern powder contaminants through machine vision due to the poor quality of images taken at production sites. Inspired by the spectral properties of crystalline polymers, this paper proposes an efficient image-based impurity detection method, which seeks to precisely and robustly detect contaminant content. Based on the changes in absorbance during polymer decomposition, a highly selective channel-weighted image enhancement approach is designed to emphasize the difference between impurities and normal particles. Then, using the prior information on the powder’s attributes, an adaptive thresholding method is employed to categorize pixels belonging to impurities. Finally, a dataset of 119 12-megapixel photos from a chemical facility, where the average size of contaminants in images is 43 pixels, is used to evaluate the performance of the proposed algorithm. The results of the detection demonstrate that the proposed strategy for image enhancement has better selectivity to impurities than typical image enhancement methods.

Chemo- and enantio-selective reversed-phase HPLC analysis of rosuvastatin using a cellulose-based chiral stationary phase in gradient elution mode

A direct reversed-phase high-performance liquid chromatographic (HPLC) method was developed for determining the content of the enantiomeric impurity of the chiral statin rosuvastatin calcium salt (RSV) in commercial tablets. The baseline enantioseparation was achieved using the Lux Cellulose-2 column and a binary linear gradient of acetonitrile and trifluoroacetic acid 0.05% in an aqueous solution. The flow rate of the mobile phases and column temperature were set at 1.0 mL min− 1 and 40 °C, respectively. In comparison with the isocratic HPLC method reported in the European Pharmacopoeia (EP) monograph for RSV, the gradient elution method offered improved chemo-and enantio-selectivity and reduced analysis times. The limits of quantitation and detection of the enantiomeric impurity were found to be 0.15 and 0.05 µg mL−1.

Simultaneous determination of l-tryptophan impurities in meat products

L-tryptophan has been used as a feed additive for swine and poultry and as a nutrient supplement for humans. However, some impurities in l-tryptophan have been reported as causative components of eosinophilia-myalgia syndrome. Therefore, from a safety perspective, it is important to analyze meat samples for these impurities. This study aims to develop an analytical method for the simultaneous detection of l-tryptophan impurities in meat products using LC–MS/MS. Among the various impurities, detection methods for (S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanoic acid (5-hydroxytryptophan) (HTP), 1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (MTCA), 3a-hydroxy-1,2,3,3a,8,8a-hexahydropyrrolo-[2,3-b]-indole-2-carboxylic acid (PIC), and 1,1′-ethylidenebistryptophan (EBT) and 2-(3-indoylmethyl)-l-tryptophan (IMT) were developed. The developed method allowed simultaneous determination of these four impurities in 5 min. No interferences from the matrix were observed, and the method showed good sensitivity to each analyte. The method detection limit and limit of quantification in meat matrices were below 11.2 and 35.7 μg/kg, respectively.

Rapid screening of pharmaceutical products for elemental impurities by a high-resolution portable energy dispersive X-ray fluorescence spectrometer using an efficient fundamental parameter method.

In this study, a rapid screening method for elemental impurities in pharmaceutical products has been established by portable energy dispersive X-ray fluorescence (EDXRF) spectroscopy combined with the efficient fundamental parameter method. The proposed method has been used for the screening of 22 elemental impurities (i.e., Cd, Pb, As, Hg, Co, V, Ni, Tl, Au, Pd, Ir, Os, Rh, Ru, Se, Ag, Pt, Sb, Mo, Cu, Sn, and Cr) in the International Conference on Harmonization (ICH) Q3D guideline. The verification of results could meet the acceptance criteria for accuracy, precision and linearity in the United States Pharmacopoeia 〈233〉. On the other hand, the limit of quantitation of the proposed EDXRF method for the screening of 22 elemental impurities in pharmaceutical products could meet the concentration limits of each element at 10 g maximum daily intake based on the established permitted daily exposure to oral drugs in the ICH Q3D guideline. Our findings open up new possibilities in the rapid screening of pharmaceutical products for the detection of elemental impurities by EDXRF, which can be expected to provide a novel, nondestructive, high-throughput, portable, and sensitive platform for the process control of elemental impurities to ensure the quality and safety of drugs.

Simplification of pharmacopoeial liquid chromatography methods for related substances of statins by hyphenated ultraviolet and charged aerosol detection

For a more comprehensive characterization of a drug substance and its impurities, multidetector approaches are a helpful tool in liquid chromatography. In particular, the relatively inexpensive hyphenation of the ultraviolet (UV) with the charged aerosol detector (CAD) extends the scope from UV-active to non- or weak chromophore analytes, respectively. In this study, the chromatographic methods of the test for related substances of simvastatin and lovastatin in the European Pharmacopoeia were adapted to UV-CAD and thus allowing a more sophisticated detection of the weak chromophore dihydro impurity besides the other UV-active impurities. The compendial gradient program for simvastatin had to be modified (lowered initial acetonitrile percentage and increased gradient slope) because an additional critical peak pair emerged with the Hypersil C18 BDS column used here. Therefore, a Plackett-Burman design with 11 factors (including 4 dummy factors) was chosen to evaluate robustness of the adapted method. The flow rate, initial acetonitrile percentage, and column temperature were identified as three critical parameters that had to be carefully observed. Finally, the validity of the method for simultaneous detection of dihydrosimvastatin with CAD and of lovastatin and simvastatin as examples of UV detection was verified according to ICH Q2 (R1). In the case of lovastatin, the direct comparison with the pharmacopoeial method reveal that a determination with CAD is the more sensitive method.

Validation of the analytical method using the energy dispersive X-ray fluorescence technique (EDXRF) for application in pharmaceutical sciences

The determination of impurities in raw materials intended for the production of pharmaceutical products is important to guarantee the quality of the final product, as well as to avoid damage to health. Metallic impurities can exhibit toxic effects even at low concentrations and so permissible levels are defined by the regulatory agencies and pharmacopeias. However, few methods are presented in official compendia in Brazil. In this sense, fast, sensitive, and precise techniques such as the energy dispersive X-ray fluorescence technique (EDXRF) must be evaluated for the analysis of metals in materials for pharmaceutical use. This way, therefore, there is the need to investigate the presence of contaminants and their concentration levels. The major goal of this research work was to validate a method for using the Energy Dispersive X-Ray Fluorescence (EDXRF) technique to identify and quantify the chemical composition of raw materials and pharmaceutical products. The methodology used was based on the selection of a microcrystalline cellulose matrix, which was spiked with two classes of contaminant elements, Class 1 (Cd, Pb, As, Hg) and Class 2A (Co, V, Ni) as defined by ICH guideline Q3D. The qualitative and quantitative analyses were carried out using the EDXRF technique, which proved to be quite effective and met all the validation parameters required in the mandatory official compendia (Resolution of the Collegiate Board (RDC) of Brazilian Health Regulatory Agency (Anvisa) nº 166, July 24, 2017), such as selectivity, linearity, precision, detection limit, quantification limit and robustness. This study showed that EDXRF can be used as a technique for detection and quantification of elemental impurities belonging to Class 1 and Class 2A.

Comprehensive multi-attribute method workflow for biotherapeutic characterization and current good manufacturing practices testing.

The multi-attribute method (MAM) is a liquid chromatography-mass spectrometry (LC-MS)-based method that is used to directly characterize and monitor numerous product quality attributes (PQAs) at the amino acid level of a biopharmaceutical product. MAM enables identity testing based on primary sequence verification, detection and quantitation of post-translational modifications and impurities. This ability to simultaneously and directly determine PQAs of therapeutic proteins makes MAM a more informative, streamlined and productive workflow than conventional chromatographic and electrophoretic assays. MAM relies on proteolytic digestion of the sample followed by reversed-phase chromatographic separation and high-resolution LC-MS analysis in two phases. First, a discovery study to determine quality attributes for monitoring is followed by the creation of a targeted library based on high-resolution retention time plus accurate mass analysis. The second aspect of MAM is the monitoring phase based on the target peptide library and new peak detection using differential analysis of the data to determine the presence, absence or change of any species that might affect the activity or stability of the biotherapeutic. The sample preparation process takes between 90 and 120 min, whereas the time spent on instrumental and data analyses might vary from one to several days for different sample sizes, depending on the complexity of the molecule, the number of attributes to be monitored and the information to be detailed in the final report. MAM is developed to be used throughout the product life cycle, from process development through upstream and downstream processes to quality control release or under current good manufacturing practices regulations enforced by regulatory agencies.

Online Detection of Impurities in Corn Deep-Bed Drying Process Utilizing Machine Vision.

Online detection of impurities content in the corn deep-bed drying process is the key technology to ensure stable operation and to provide data support for self-adapting control of drying equipment. In this study, an automatic approach to corn image acquisition, impurity classification and recognition, and impurities content detection based on machine vision technology are proposed. The multi-scale retinex with colour restore (MSRCR) algorithm is utilized to enhance the original image for eliminating the influence of noise. HSV (Hue, saturation, value) colour space parameter threshold is set for image segmentation, and the classification and recognition results are obtained combined with the morphological operation. The comprehensive evaluation index is adopted to quantitatively evaluate the test results. Online detection results show that the comprehensive evaluation index of broken corncobs, broken bracts, and crushed stones are 83.05%, 83.87%, and 87.43%, respectively. The proposed algorithm can quickly and effectively identify the impurities in corn images, providing technical support and a theoretical basis for monitoring impurities content in the corn deep-bed drying process.

Analytical profile of the lysergamide 1cP-AL-LAD and detection of impurities.

The development of novel lysergamides continues to occur, based on both the needs of psychedelic medicine and commercial interest in new recreational substances. The present study continues the authors' research on novel lysergamides and describes the analytical profile of 1-cyclopropanoyl-AL-LAD (IUPAC name: 1-(cyclopropanecarbonyl)-N,N-diethyl-6-(prop-2-en-1-yl)-9,10-didehydroergoline-8β-carboxamide; 1cP-AL-LAD), using various chromatographic, mass spectrometric, and spectroscopic methods. Analysis of a powdered sample of 1cP-AL-LAD, obtained from an online vendor, by high performance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry in full scan/AutoMS/MS mode revealed the detection of 17 impurities based on high-resolution tandem mass spectral data; tentative determination of their identity was based on mass spectral grounds alone, though detection of AL-LAD and 1P-AL-LAD was confirmed using available reference standards. Other tentative compound identifications included 1-acetyl-AL-LAD and several other substances potentially reflecting oxidation of the N6 -allyl group as well as other positions on the ergoline ring system. These data may assist those interested in the chemistry of lysergamides. Finally, 1cP-AL-LAD was also detected in samples of "blotters" sold online for recreational use.

Method Development for Reversed-Phase Separations of Peptides: A Rational Screening Strategy for Column and Mobile Phase Combinations with Complementary Selectivity

This review article summarizes the results obtained from the combined efforts of a joint academic and industrial initiative to solve the real-life challenge of determining low levels of peptide-related impurities (typically 0.05–1% of the drug substance) in the presence of the related biologically active peptide at a high concentration. A rational screening strategy for pharmaceutically important peptides has been developed that uses combinations of reversed‑phase ultrahigh-pressure liquid chromatography (UHPLC) columns and mobile phases that exhibit complementary reversed-phase chromatographic selectivity using either UV- or mass spectrometry (MS)-compatible conditions. Numerous stationary and mobile phases were categorized using the chemometric tool of principal component analysis (PCA), employing a novel characterization protocol utilizing specifically designed peptide probes. This was successfully applied to the development of a strategy for the detection of impurities (especially isomers) in peptide drug substances using two-dimensional liquid chromatography coupled with MS detection (2D-LC–MS).

Measuring material velocity and thickness mapping of flax fiber-reinforced plastic composites using automated ultrasonic rapid motion scanner

The interest in using sustainable materials was a part of the Sustainable Development Goals by the United Nations in 2015, its mission aims to eradicate poverty and conserve the environment by the year 2023. The use of engineered bio-fiber has the potential to replace the usage of synthetic fibers. However, the diversification of the application is limitless. The intended paper investigates the detection of impurities of cured pre-impregnated bio-composite using C-scan ultrasound. The Flax Fiber-Reinforced Plastic Composites were fabricated and cured with heat-assisted curing. The panels were inspected by an automatic ultrasonic rapid motion scanner to measure the material sound velocity of the Flax panel. As a result, the test obtained a reference value of Flax Fiber-Reinforced Plastic Composite material sound velocity of 3.17 (31700 mm/s) for thickness mapping. The obtain sound velocity value can be used as a future reference for inspecting any type of flax material specimen by using the rapid motion scanner from Eddyfi Technologies.

Features and Practical Aspects of Radiochemical Purity Determination of Receptor-Specific Lu-177 Radiopharmaceuticals as Exemplified by [<sup>177</sup>Lu]Lu–PSMA-617

Radiochemical purity (RCP) is one of the key quality criteria for radiopharmaceuticals (RPs) used in clinical practice. The results of RCP measurements depend on the analytical technique, as well as detection parameters, which are specific to a particular analytical system. When reviewing literature data on the synthesis, pharmaceutical development, preclinical and clinical trials of the same radiopharmaceutical by different authors, one may note significant variability in the RCP values obtained. Hence, it is important to carefully select analysis parameters and study their influence on the results. The aim of the study was to compare previously published and self-developed procedures for RCP analysis of 177 Lu-RPs in terms of their efficiency in the detection and quantification of possible radiochemical impurities, as well as to determine the analytical system parameters that have a significant impact on the interpretation of the analysis results, using [ 177 Lu]Lu–PSMA-617 as a case study. Materials and methods : the study used samples of [ 177 Lu]Lu–PSMA-617 with a volume activity of lutetium-177 of 150–4800 MBq/mL, containing 10–100 µmol/L of the PSMA-617 precursor and 30 mmol/L of sodium acetate as a buffering solution (pH 4.5). The samples were tested by high-performance liquid chromatography (HPLC) and thin-layer chromatography in the conditions described in the literature and developed in the course of the work. Results : the study showed a significant influence of the chosen analytical procedure on the results of [ 177 Lu]Lu–PSMA-617 RCP assessment. The profile of possible radiochemical impurities requires the use of high-resolution HPLC techniques. Conclusions : the analytical procedure developed and applied by the authors is quite effective. The results of RCP assessment are influenced by the detection system parameters, such as the length and inner diameter of the flow cell and the means of analytical signal processing (peak extraction parameters, smoothing parameters, and noise subtraction/suppression). This fact necessitates validation considering the characteristics of a particular analytical system and demonstrates the need to assess interlaboratory precision in the framework of the implementation and verification of analytical procedures.

In situ detection of multitarget impurities on contact lens by electrochemical scanning probe

Identifying multitarget impurities on contact lenses is challenging because traditional methods such as polymerase chain reaction cannot be used on the unknown target. Other sampling methods often require expensive antibodies or dyes. Therefore, this research focuses on the detection of multitarget impurities in situ on the lens surface as a more innovative and effective label-free assay using scanning electrochemical microscopy (SECM). Impurities were investigated using an electrochemical assay and an oxygen consumption assay. The electrochemical activity of BSA and the bacteria adhered to the contact lenses was explored using a FcMeOH solution. The experimental results revealed the difference in current values of the clean and protein-adsorbed contact lens samples. Furthermore, SECM can be used to detect the oxygen consumption of aerobic microbes using the oxygen reduction method. Thus, contaminated microbes can be identified without labeling in phosphate buffer saline. The mass spectra of the contact lenses were studied and the adsorption of impurities was verified. Finally, contact lens samples were investigated from various patients with ocular infection diagnosed with corneal ulcers, preseptal cellulitis, and orbital cellulitis. As a result, SECM could be a new tool for distinguishing the cleanliness of contact lenses in the future.